Method and composition for treating neurodegenerative disorders

Abstract

The invention provides compositions and methods for treating neurodegenerative disorders. A method of the invention involves administering to an individual in need of treatment a composition having an R-NSAID and an NMDA antagonist. Another method of the invention involves administering to an individual in need of treatment a composition having at least two compounds that are capable of interacting with CYP2C9, wherein at least one of said compounds is an Aβ 42 lowering agent. The methods and compositions of the invention are useful for treating and preventing neurodegenerative disorders like Alzheimer's disease, dementia, mild cognitive impairment.

1 . A pharmaceutical composition comprising an R-NSAID and a NMDA antagonist.  
     
     
         2 . The composition of  claim 1  wherein said R-NSAID is selected from the group consisting of R-flurbiprofen, R-ketoprofen, R-ketorolac, R-naproxen, R-tiaprofenic acid, R-suprofen, R-carprofen, R-pirprofen, R-indoprofen, R-benoxaprofen, and R-etolodac.  
     
     
         3 . The composition of  claim 2  wherein said NMDA antagonist is selected from the group consisting of memantine, adamantane, amantadine, an adamantane derivative, dextromethorphan, dextrorphan, dizocilpine, ibogaine, ketamine, remacemide, and phencyclidine.  
     
     
         4 . The composition of  claim 3  wherein said R-NSAID is R-flurbiprofen.  
     
     
         5 . The composition of  claim 3  wherein said NMDA antagonist is memantine.  
     
     
         6 . The composition of  claim 4 , comprising an amount of R-flurbiprofen or pharmaceutically acceptable salt or ester thereof when administered in a single dose to a fasting individual sufficient to produce a plasma C max  of about 25-150 μg per mL per dose.  
     
     
         7 . A method of treating Alzheimer's disease comprising (a) identifying a patient having Alzheimer's disease and (b) administering to said patient an Alzheimer's disease treating effective amount of the composition of  claim 1 .  
     
     
         8 . The method of  claim 7  wherein said R-NSAID is R-flurbiprofen.  
     
     
         9 . The method of  claim 7  wherein said NMDA antagonist is memantine.  
     
     
         10 . The method of  claim 7  further comprising administration of an acetylcholine esterase inhibitor.  
     
     
         11 . The method of  claim 8  wherein said Alzheimer's disease treating effective amount of R-flurbiprofen is from about 50 mg to about 1800 mg per day and the Alzheimer's disease treating effective amount of memantine is from about 0.5 mg to about 30 mg per day.  
     
     
         12 . A composition comprising two compounds that are capable of interacting with CYP2C9, wherein at least one of said compounds is an Aβ 42  lowering agent.  
     
     
         13 . The composition of  claim 12 , comprising: 
 flurbiprofen or a derivative of flurbiprofen selected from the group consisting of a nitrosated flurbiprofen, a nitrosylated flurbiprofen, 2-(2′-fluro-4-biphenylyl)propionic acid, a nitrosated or nitrosylated 2-(2′-fluro-4-biphenylyl)propionic acid, 2-(2,2′-difluroro-4-biphenylyl)propionic acid, a nitrosated or nitrosylated 2-(2,2′-difluroro-4-biphenylyl)propionic acid, and pharmaceutically acceptable salts and ester thereof; and    an interactor of CYP2C9 selected from the group consisting of diclofenac, ibuprofen, meloxicam, naproxen, piroxicam, suprofen, celicoxib, tolbutamide, glipizide, losartan, irbesartan, amitriptyline, fluoxetine, fluvastatin, phenyloin, rosiglitazone, tamoxifen, torsemide, S-warfarin, naphthalene, amiodarone, atorvastatin, cerivastatin, fluconazole, fluvastatin, fluvoxamine, isoniazid, lovastatin, paroxetine, phenylbutazone, probenicid, sertraline, simvastatin, sulfamethoxazole, sulfaphenazole, sulphinpyrazone, teniposide, trimethoprim, zafirlukast, and rosuvastatin, and pharmaceutically acceptable salts or esters thereof.    
     
     
         14 . The composition of  claim 12  comprising: 
 R-flurbiprofen or a pharmaceutically acceptable salt or ester thereof; and    a statin that is an interactor of CYP2C9 or a pharmaceutically acceptable salt or ester thereof.    
     
     
         15 . The composition of  claim 14 , wherein said statin is fluvastatin or rosuvastatin, or a pharmaceutically acceptable salt or ester thereof.  
     
     
         16 . The composition of  claim 15 , comprising an amount of from about 1 mg to about 1600 mg of R-flurbiprofen or pharmaceutically acceptable salt or ester thereof.  
     
     
         17 . A method of treating Alzheimer's disease comprising (a) identifying a patient having Alzheimer's disease and (b) administering to said patient an Alzheimer's disease treating effective amount of the composition of  claim 12 .  
     
     
         18 . The method of  claim 17  wherein said composition comprises an Alzheimer's disease treating effective amount of: 
 R-flurbiprofen or a pharmaceutically acceptable salt or ester thereof, and    a statin that is an interactor of CYP2C9 or a pharmaceutically acceptable salt or ester thereof.    
     
     
         19 . The method of  claim 17  further comprising administration of an acetylcholine esterase inhibitor.  
     
     
         20 . The method of  claim 18  wherein said an Alzheimer's disease treating effective amount of R-flurbiprofen is from about 1 mg to about 1600 mg per day.